Vaccine-Preventable Diseases

Typhoid

Typhoid fever is caused by Salmonella typhi, which differs from most other Salmonella species in that it infects only humans and frequently causes severe systemic illness. The organism is generally transmitted via food contaminated with the feces or urine of people with the disease or those who are S. typhi carriers. The fatality rate is approximately 16% for untreated cases and 1% for those given appropriate antibiotic therapy. Between 2% and 5% of typhoid cases become chronic carriers, sometimes shedding bacteria in stool for years. The risk of severe illness is increased in people with depressed immunity (e.g., due to HIV) or decreased gastric acid levels.

Epidemiology

In endemic areas (such as Africa, Asia, Central and South America), typhoid fever has long been considered a disease with the greatest impact in individuals 5 to 19 years of age. Age-specific incidence rates vary from one country to another, however, and significant illness and deaths have been reported in children < 5 in some settings. Reports of typhoid fever in children < 2 years of age are quite unusual. Several factors may contribute to this apparently lower risk in very young children, including age-specific changes in the immune response, atypical or milder disease in this population and under-reporting. Whatever the cause(s), the observation is important in light of our incomplete knowledge of vaccine immunogenicity and efficacy in this age group.

The incidence of typhoid fever is very low in the industrialized world. An average of 70 cases have been reported annually in Canada over the past 5 years. The low incidence rates in industrialized countries is attributable to overall good living conditions, in particular the high quality of drinking water and the treatment of sewage. The rates were achieved without vaccines, and vaccination has no ongoing role in their maintenance.

The greatest risk of typhoid infection for Canadians occurs while they are travelling in countries or regions of countries where sanitation is likely to be poor. However, not all travellers in these countries or regions are at markedly increased risk. Indeed, the risk of suffering from typhoid fever in many settings in developing countries is minimal (e.g., business-class hotels, conference centres and resort hotels). The greatest risk appears to be associated with exposures to food and water in uncontrolled settings (e.g., market stalls, street vendors, home restaurants and family settings). Even relatively short visits with friends and family can put Canadian travellers (the so-called VFR or “visiting friends and relatives” group) at substantial risk of typhoid in some areas.

Regardless of the setting, typhoid immunization is not a substitute for careful selection and handling of food and water. The available vaccines provide only 50% to 60% protection and do not prevent disease in those who ingest a large number of organisms. However, immunization may reasonably be expected to reduce the risk of typhoid fever among otherwise healthy travellers in areas where this disease is either endemic or epidemic.

Preparations Licensed for Immunization

Two typhoid vaccines are currently available for protection against typhoid fever.

Parenteral, capsular polysaccharide vaccine

This vaccine is an injectable solution of Vi (virulence) antigen prepared from the capsular polysaccharide (ViCPS) of S. typhi strain TY2. The vaccine is produced by Aventis Pasteur and distributed in Canada under the name of Typhim Vi^TM. Each 0.5 mL dose of vaccine contains 25 µg of purified polysaccharide.

Oral, live attenuated vaccine

Ty21a is an attenuated strain of S. typhi that was produced by chemical mutagenesis. This bacterium has lost some virulence factors and replicates for only a limited period of time in human hosts. The vaccine is produced by Swiss Serum and Vaccine Institute and is supplied either as enteric-coated capsules (four doses containing lyophilized bacteria) or as foil sachets (three doses of lyophilized bacteria). Although both formulations are available at this time, it is likely that the capsular form will be eclipsed by the simpler, sachet form in the coming years. Both formulations contain buffer to enhance passage of the attenuated bacteria through the gastric acid barrier. The components included in these vaccines are listed in the Table.

Efficacy and Immunogenicity

Parenteral, capsular polysaccharide vaccine

The parenteral vaccine stimulates a specific antibody response (i.e., ≥ fourfold rise in antibody titre) in about 93% of healthy adults. Controlled trials have demonstrated that the serologic response to vaccine is correlated with protective efficacy. Two randomized, double-blind, controlled field trials of ViCPS in disease-endemic areas have demonstrated protective efficacy rates of 55% (95% confidence interval [CI] 30%-71%). The efficacy of immunization with ViCPS has not been systematically studied in people from industrialized countries who travel to disease-endemic regions or in children < 5 years of age. ViCPS has not been tested among children < 1 year of age. Its protective efficacy in people previously immunized with earlier parenteral formulations or the oral vaccine is unknown. Although antibody titres fall with time after vaccination, immunity following Typhim Vi^TM is thought to last for 2 to 3 years.

In some regions of the world, virulent but Vi-negative strains of S. typhi have been reported. Typhim Vi^TM would not be expected to protect against these rare isolates. Novel conjugated Vi vaccines that have enhanced efficacy in adults and children may soon be available.

Oral, live attenuated vaccine

The Ty21a vaccines stimulate a cell-mediated immune response as well as inducing both secretory and humoral antibody. Healthy subjects do not shed vaccine-strain organisms in their stool. As a result, secondary transmission to contacts does not occur. Despite the limited capacity of the vaccine-strain organism to replicate, individuals who are significantly immunocompromised should not receive oral vaccine.

In studies delivering at least three doses of the capsular form of the vaccine in typhoid endemic regions, a protective efficacy of 51% (95% CI 35%-63%) can be expected. Although less information is available about the liquid formulation in field trials, the available data suggest that this vaccine is at least as effective as the capsular form. The oral vaccines appear to be less effective for disease prevention in children 5 to 9 years of age (17%-19%) than older children (54%-72% among 10 to 19 year olds). Protective antibodies after the administration of three doses of vaccine are detectable for 3 to 4 years and may persist for longer periods in some individuals.

There are no data on the efficacy or duration of protection in travellers from industrialized countries or in children < 5 years of age (capsular formulation) or < 3 years of age (liquid formulation). Neither are there reports regarding the protective efficacy of the oral formulations in people previously immunized with parenteral vaccines. The activity of the Ty21a vaccines against the rare Vi-negative isolates is unknown.

Recommended Usage

Routine typhoid immunization is not recommended in Canada. However, selective immunization should be considered in the following groups:

• Travellers who will have prolonged (> 4 weeks) exposure to potentially contaminated food and water, especially those travelling to or working in small cities, villages or rural areas in countries with a high incidence of disease. Individuals billeted with or visiting families in such areas may be at particularly high risk. Immunization is not routinely recommended for business travel or short-term (< 4 weeks) holidays in resort hotels in such countries.

• Travellers with reduced or absent gastric acid secretion.

• People with ongoing household or intimate exposure to an S. typhi carrier.

• Laboratory workers who frequently handle cultures of S. typhi. Technicians working in routine microbiology laboratories do not need to receive this vaccine.

Typhoid immunization is not routinely recommended for workers in sewage plants, for controlling common-source outbreaks, for people attending rural summer or work camps or for people in nonendemic areas experiencing natural disasters such as floods. It is not recommended for the control or containment of typhoid outbreaks in Canada. Typhoid vaccine does not confer complete protection against disease, and immunity may be overwhelmed by a large inoculum of S. typhi. Therefore, it is necessary to warn travellers that immunization is only an additional preventive measure against typhoid fever in high-risk situations and that care in the selection of food and water remains of primary importance.

Route of Administration and Storage

Parenteral, Vi capsular polysaccharide vaccine

Adults and children > 2 years of age should receive a single dose of 0.5 mL (25 µg) intramuscularly. The optimum interval for booster doses has not been established, but the manufacturer recommends booster doses every 3 years if continued or renewed exposure is expected. There are no data on the use of this vaccine as a booster for people who have received other vaccines previously. However, a single dose of the vaccine at the appropriate interval should re-establish protection.

Oral typhoid vaccine (Ty21a) - capsular formulation

For adults and children > 5 years of age, one enteric-coated capsule (Vivotif™, Berna Vaccine) should be taken on alternate days to a total of four capsules. Each capsule should be taken on an empty stomach with a liquid no warmer than 37° C. The capsules should be kept refrigerated (at a temperature of 2° C to 8° C) until used. Although refrigeration is recommended, this formulation is stable for up to 7 days at 20° C to 25° C. All four capsules must be taken for optimal protection.

Oral typhoid vacine (Ty21a) - liquid formulation

The liquid preparation (Vivotif L™, Berna Vaccine) is licensed for adults and children > 3 years of age. Each package contains three foil sachets with lyophilized vaccine in one half and buffer in the other half. The contents of both halves of one sachet must be mixed with liquid no warmer than 37°C, and the diluted vaccine-buffer mix should be taken on an empty stomach. This procedure is repeated on alternate days for a total of three doses. The sachets should be kept refrigerated (at a temperature of 2°C to 8°C) until used. Although refrigeration is recommended, this formulation is stable for at least 48 hours at 20°C to 25°C in the sachets. The vaccine is less stable once reconstituted, and should be drunk immediately upon reconstitution (within 1 hour). All three doses must be taken for optimal protection.

Booster Doses

Relatively few data are available to guide recommendations for either the frequency or timing of booster doses in Canadians residing abroad and in travellers. Nonetheless, periodioc booster doses in those at continued risk may reasonably be expected to increase antibody titres and protection (e.g., every 2-3 years for the parenteral formulation and every 7 years for the oral formulations). Although there are no data regarding the interchangeability of typhoid vaccines, it is presumed that boosting can be performed with any of the available formulations regardless of the vaccine used initially.

Simultaneous Administration with Other Vaccines

Although all possible combinations have not been specifically studied, there is no known interaction between the ViCPS vaccine and a number of other relevant travel vaccines such as hepatitis A vaccine, yellow fever vaccine and hepatitis B vaccine. The liquid form of the oral typhoid vaccine can be given simultaneously with oral cholera vaccine, and such a combined formulation is now available (ColertifBerna)*. Administration of the capsular form of the oral vaccine should be separated from administration of the oral cholera vaccine by at least 8 hours. Other combination formulations targeting travellers (e.g., hepatitis A vaccine with typhoid Vi) will likely become available in the near future.

* Such a combined formulation is not now available, and the manufacturer has no plans to make such a product available.

Comments Applicable to Both Oral Formulations

Minor variations in dosing schedule are not expected to affect the efficacy of either of the oral typhoid formulations. However, if it is deemed necessary to repeat the series because of long intervals between doses (> 4 days), the administration of an additional full course of vaccine would not be harmful. Although compliance can be an issue with these products, since they are self administered, recent evidence suggests that most travellers take the vaccines competently if properly instructed.

Adverse Reactions

The parenteral ViCPS vaccine is far less reactogenic than the previous parenteral (whole bacterium) product. A recent meta-analysis suggests that local reactions (e.g., pain, redness, swelling) can be expected in approximately 4% of vaccinees (95% CI 1.3%-10%), whereas only about 1% report systemic effects such as fever (95% CI 0.1%-12.3%). Virtually all of the available data regarding adverse events following immunization with the Vi polysaccharide vaccine have been acquired in studies of children and young adults (age < 25 years).

The reported adverse events following oral immunization are also relatively rare and mild. Local reactions, such as vomiting (2.1%: 95% CI 0.6%-7.8%) and diarrhea (5.1%: 95% CI 1.7%-14.5%), seldom prevent completion of the course of immunization. Low grade fever can be expected in approximately 2% of vaccinees (95% CI 0.7%-5.3%). Recent case reports raise the possibility that the Ty21a vaccines may, very rarely, predispose vaccinees to reactive arthritis.

Contraindications and Precautions

The only contraindication to administration of the parenteral ViCPS vaccine is a history of a severe local or systemic reaction to a previous dose of this vaccine. Similarly, the oral live typhoid vaccine is contraindicated in subjects with hypersensitivity to any component of the vaccine or the enteric-coated capsule. The oral vaccines should not be given to anyone with an acute gastrointestinal condition or inflammatory bowel disease.

Pediatric use

The ViCPS vaccine can be used in children > 2 years of age. The capsular form of the oral vaccine can be used in children > 5 years of age (if they can be induced to swallow the rather large capsules). The liquid formulation of the oral vaccine can be used in children > 3 years of age. As noted above, there is some controversy regarding the frequency and severity of typhoid fever in children < 5 years of age.

Immunization in pregnant women and nursing mothers

Although the highly purified ViCPS vaccine would not be expected to have any adverse effects, its safety in pregnancy has not been directly studied. Therefore, the benefits of vaccine must be carefully weighed against any potential adverse effects before it is given to pregnant women. Oral typhoid vaccines should not be given to pregnant women. Although there are no data, it is reasonable to assume that either vaccine could be used safely in nursing mothers.

Immunization in immunocompromised hosts

The oral vaccines should not be given to immunocompromised or immunosuppressed people, including those with known HIV infection. Safe storage should be emphasized in households with small children and immunocompromised individuals. Note that these concerns for immunocompromised hosts are purely theoretical, and no case of disseminated infection with the attenuated bacterium has been reported. The limited capacity of the attenuated strain to replicate in the human host is independent of the host's immune status.

Summary of Recommendations

• Both inactivated and oral typhoid vaccines can provide some degree of protection against typhoid fever in children and young adults in typhoid endemic regions.

• These vaccines are also likely to be useful in Canadians returning for family visits in their countries of origin and in Canadian travellers who spend prolonged periods of time in endemic areas.

• Both inactivated and oral typhoid vaccines are likely to provide at least some degree of protection against typhoid fever in subjects who travel from non-endemic regions to endemic regions.

• Individuals with decreased gastric acid barriers (e.g., achlorhydria, medications that reduce gastric acidity, antacid abuse) who travel to typhoid endemic regions should be offered either parenteral or oral immunization.

• Immunocompromised subjects and pregnant women for whom typhoid immunization is advisable should receive the parenteral vaccine.

• Typhoid immunization may also reasonably be considered in a control program to limit a typhoid fever epidemic (e.g., in closed communities, refugee settings).

• Booster doses of a typhoid vaccine for Canadians residing abroad and frequent travellers should be considered every 2 to 3 years for the parenteral formulation and every 3 to 4 years for the oral formulations.

• Typhoid vaccines can be considered to be interchangeable for booster doses.

• Typhoid immunization is not recommended for the large majority of business travellers and short-term holiday travellers.

• Typhoid immunization in non-travelling Canadians is ONLY recommended for individuals regularly working with this organism in clinical or research laboratories and in family members and close contacts of a chronic carrier of S typhi.

• Typhoid immunization may also provide some degree of protection in children as young as 2 (inactivated vaccine) or 3 (liquid formulation oral vaccine) years of age when these children will be staying with families abroad or will be travelling for prolonged periods of time in endemic areas.

Selected References

Acharya IL, Lowe CU, Thapa R et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. N Engl J Med 1987;317:1101-04.

Barnett ED, Chen R. Children and international travel: immunizations. Pediatr Infect Dis J 1995;14:988-89.

CDC. Typhoid immunization recommendations of the Advisory Committee on Immunization Practices (ACPI). MMWR 1994;43:RR-14.

Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on overseas travelers and typhoid. CCDR 1994;20:61-2.

Cryz SJ Jr. Post-marketing experience with live oral Ty21a vaccine. Lancet 1993;341:49-50. Cryz SJ Jr. Patient compliance in the use of Vivitif Berna™ vaccine, typhoid vaccine, live oral Ty21a. J Travel Med 1998;5:14-17.

Engels EA, Falagas ME, Lau J et al. Typhoid fever vaccines: a meta-analysis of studies on efficacy and toxicity. BMJ 1998;316:110-16.

Engels EA, Lau J. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev 2000;2:CD001261.

Horowitz H, Carbonaro CA. Inhibition of the Salmonella typhi oral vaccine strain, TY21a, by mefloquine and chloroquine. J Infect Dis 1992;166:1462-64.

Ivanoff B, Levine MM, Lambert PH. Vaccination against typhoid fever: present status. Bull WHO 1994;72:957-71.

Keitel WA, Bond NL, Zahradnik JMB et al. Clinical and serological responses following primary and booster immunization with Salmonella typhi Vi capsular polysaccharide vaccines. Vaccine 1994;12:155-59.

Klugman KP, Gilbertson IT, Koornhof HJ et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet 1987;2:1165-69.

Levine MM, Ferrecio C, Black RE et al. Comparison of enteric coated capsules and liquid formulation of Ty21a typhoid vaccine in randomized controlled field trial. Lancet 1990;2:891-94. Levine MM, Ferrecio C, Black RE et al. Large scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation. Lancet 1987;1:1049-52.

Levine MM, Taylor DN, Ferrecio C. Typhoid vaccine comes of age. Pediatr Infect Dis J 1989;8:374-81.

Levine MM, Ferrecciio C, Abrego P et al. Duration of efficacy of Ty21a, attenuated Salmonella typhi live oral vaccine. Vaccine 1999;17:S22-27.

Lin FY, Ho VA, Khiem HB et al. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five year old children. N Engl J Med 2001;344:1322-3.

Mahle WT, Levine MM. Salmonella typhi infection in children younger than 5 years of age. Pediatr Infect Dis J 1993;12:627-31.

Sinha A, Sazawal S, Kumar R et al. Typhoid fever in children aged less than 5 years. Lancet 1999;354:734-37.

Taylor DN, Levine MM, Kuppens L et al. Why are typhoid vaccines not recommended for epidemic typhoid fever? J Infect Dis 1999;180:2089-90.